tbuckley/cabot-search huggingface dataset:
A phase 2 study of trametinib for patients with pediatric glioma or plexiform neurofibroma with refractory tumor and activation of the MAPK/ERK pathway.
Authors: Sébastien Perreault, Dorsa Sadat Kiaei, Mathieu Dehaes, Valérie Larouche, Uri Tabori, Cynthia Hawkin, Sarah Lippé, Benjamin Ellezam, Edith Cantin, Marie-Ève Routhier, Maxime Caru, Stephanie Vairy, Geneviève Legault, Eric Bouffet, Vijay Ramaswamy, Hallie Coltin, Lucie Lafay-Cousin, Juliette Hukin, Craig Erker, Nada Jabado
Journal: Journal of Clinical Oncology (2022)

2042 Background: Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children and the majority of PLGG have activation of the MAPK/ERK pathway. Plexiform neurofibromas (PN) are found in up to 50% of patients with neurofibromatosis type 1 (NF1). Trametinib has been used widely to treat PLGG and PN, but no clinical trial has reported its efficacy. Methods: This multicenter phase II trial includes patients aged ≥ 1 month to ≤ 25 years with progressing/refractory PLGG groups or PN. The primary objective was to evaluate the overall response rate after daily oral trametinib administration for eighteen 28-day cycles. Results: As of January 31 st , 2022, 60 patients with PLGG and 45 patients with PN have been enrolled. Median age is 9.5 years (range 1.8-25.4) for PLGG and 11 years (range 0.7-19.8) for PN. Median follow-up is 18 months (range 0.1-38.1). Fifty-three patients with PLGG were evaluable. The overall response includes: 1 complete response (CR) (1.9%), 7 partial response PR (13.2%), 17 minor response MR (32.1%), 23 stable disease (SD) (43.4%) and 5 progressive disease (PD) (9.4%). Twenty-eight patients with a total of 32 PN were available for volumetric analysis. Volumetric assessment demonstrated an overall response rate of 60.7% compared to 24.1% when using RECIST 1.1 and 62.5% of PN showed a decrease of more than 20% in volume. Median volume change was a decrease of 30% (range -93.5 to 14.3). A total of 59 (69.4%) patients discontinued treatment as planned after 18 cycles and 9 (10.6%) patients had to stop trametinib due to adverse events. Conclusions: Response rates observed in our study suggest that trametinib is a potentially effective targeted therapy for patients with recurrent/refractory PLGG and PN. Treatment was overall well tolerated. This trial will continue to gather data on duration of response and long-term outcome for PLGG and PN treated with trametinib. Clinical trial information: NCT03363217.
Rural cancer care access in the United States: A worsening problem?
Authors: James Edward Bates, Christina Henson
Journal: Journal of Clinical Oncology (2022)

e18521 Background: Rural counties have a decreased incidence of cancer relatively to non-rural counties; however, they have higher death rates from cancer. This disparity in death rates is worsening. Patients in rural areas face significant barriers to accessing oncologic care – limited access to oncologic providers and significant travel distances to treatment chief among them. We aimed to assess trends in geographic distribution of medical and radiation oncologists to ascertain trends in access to oncologic specialists in rural areas. Methods: We used the Medicare Physician &amp; Other Practitioners database published by the Centers for Medicare &amp; Medicaid Services from 2013 and 2019 (the earliest and latest available) to identify radiation oncologists and medical oncologists (including hematology/oncology) based on the Provider Type field. We used the Rural Urban Commuting Area Codes as defined by the US Department of Agriculture; rural was defined as non-metropolitan areas with a &lt; 30% commuting flow to a large urban center consistent with the definition from the WWAMI Rural Health Research Center. The US Health Resources &amp; Services Administration, using a similar definition, defines 19.7% of the US population as rural. Results: In 2013, we identified 10,440 medical oncologists and 4,292 radiation oncologists in the United States. 7.6% of medical oncologists and 8.9% of radiation oncologists practiced in rural areas. In 2019, 7.4% of medical oncologists and 8.5% of radiation oncologists practiced in rural areas (Table). There were 1,430 more medical oncologists practicing in 2019 as compared to 2013; only 83 (5.8%) practice in a rural area. There were 436 additional radiation oncologists with only 21 (4.8%) practicing in a rural area. Growth in both medical oncologists (χ 2 = 8.47, p = 0.02) and radiation oncologists (χ 2 = 8.47, p = 0.004) was more likely to be in urban than rural areas. Conclusions: While disparities in oncologist distribution along the rural-urban continuum are well known, we establish that these disparities are becoming more pronounced despite increasing awareness. This raises concern that disparities in cancer outcomes in rural patients will continue to worsen. Alternative strategies to increases access to cancer care in rural areas are critical.[Table: see text]
Promising clinical benefit rates in advanced cancers alongside potential biomarker correlation in a phase I/II trial investigating bexmarilimab, a novel macrophage-guided immunotherapy.
Authors: Petri Bono, Annika Pasanen, Loic Verlingue, Maja J.A. de Jonge, Maria J. de Miguel, Tanja Skytta, Sanna Iivanainen, Shishir Shetty, Yuk Ting Ma, Donna M. Graham, Sukeshi Patel Arora, Panu Jaakkola, Christina Yap, Sirpa Jalkanen, Maija Hollmen, Jussi Koivunen, Anna Rachel Minchom
Journal: Journal of Clinical Oncology (2022)

2645 Background: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-CLEVER-1 IgG4-antibody capable of inducing a phenotypic M2 to M1 immune switch of tumor-associated macrophages. Methods: MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a first-in-human phase I/II study (NCT03733990) to assess safety and preliminary efficacy of Bexmarilimab in patients with refractory advanced solid tumours. Part I has been completed with initial good safety profile of the IMP, preliminary signs of efficiency, and recommended dose of 1mg/kg Q3W for part II (ESMO 2020). In Part II (ESMO 2021), 10 distinct solid tumour types were enrolled to assess preliminary efficacy (overall survival (OS), progression free survival (PFS), and clinical benefit rate (CBR). Clever-1 IHC in pre-treatment biopsies with Ventana platform using a primary antibody 4G9 (Santa Cruz) was scored by % of positive cells compared to the viable tumor cells. Results: At the Jan 2022, a total of 193 patients have been enrolled to the study. In the completed cohorts, 138 patients have received 1-21 doses (median 3) of Bexmarilimab Q3W. Bexmarilimab was well tolerated, and no new safety signals were detected. Part I and Part II fully enrolled 11 cancer cohorts, the median PFS was 2.0 months (95% CI 1.9 – 2.0) and the median OS was 5.2 months (95% CI 4.3 – 6.4). CBR for Part II was 17.3% (19/110) at cycle 4 of treatment (by RECIST v.1.1). Notably, 30-40% CBR at cycle 4 was seen in cutaneous melanoma (30%), gastric cancer (30%), cholangiocarcinoma (30%), hepatocellular cancer (40%), and ER+ breast cancer (40%). Six-month survival rates (landmark analysis) were 70.1% for CBR compared to 34.7% for non-CBR patients, with a similar duration of prior therapy in both groups. Preliminary biomarker analysis (n = 77) demonstrated positive trend (p = 0.038) between CBR and higher intratumoral Clever-1 positivity (median of 15% positivity (range 0-25) in CBR and 3% (range 0-85) in non-CBR patients) Conclusions: Bexmarilimab continues to demonstrate promising anti-tumour activity as a monotherapy in several refractory solid tumours. Furthermore, preliminary biomarker analysis suggests a possibility for patient selection based on tumour Clever-1 expression. Further expansion of the study will investigate optimal dosing and biomarkers of efficacy. Clinical trial information: NCT03733990.
Association between tumor burden and response to immunotherapy in patients with metastatic renal cell carcinoma.
Authors: Hesham Abdallah Yasin, Yu-Wei Chen, Matthew D Tucker, Katy Beckermann, Kerry Schaffer, Nancy B. Davis, Renee McAlister, Deborah Wallace, Elizabeth Kaiser, Brian I. Rini
Journal: Journal of Clinical Oncology (2022)

4541 Background: Immunotherapy (IO) has become the standard of care in patients with metastatic renal cell carcinoma (mRCC), yet clinical biomarkers of outcome remain elusive. Preclinical and clinical studies have demonstrated that a lower tumor volume burden is associated with better response to IO in melanoma and lung cancer. Methods: Retrospective chart review of mRCC patients treated with Immunotherapy/Immunotherapy or Immunotherapy/Tyrosine kinase inhibitors (TKI) combinations at Vanderbilt Ingram Cancer Center was conducted. Baseline target tumor lesions including primary kidney tumors and treatment response were assessed by RECIST 1.1 criteria. The association between baseline tumor burden and outcomes of interest [progression-free survival (PFS) and overall survival (OS)] were assessed with multivariable Cox regression model. Results: 79 patients with mRCC were included in the cohort. The median age was 64, 80% were male, 82% had clear cell histology, and 73% were IMDC intermediate/poor risk group. 53% received IO/IO and 39% received IO/TKI. 71% had prior nephrectomy and 14% had prior systemic therapy. The median baseline tumor burden was 87 mm (range: 16-363 mm). After adjusting for age, gender, histology, prior nephrectomy/systemic therapy and IMDC risk, baseline tumor burden was not associated with either PFS (p-value: 0.42) or OS (p-value: 0.99). At the initial follow-up scan (median time of 3.1 months from treatment initiation) 22 (28%) patients had an objective response and 41 (52%) patients had stable disease. Among patients with tumor shrinkage, every 10% decrease seen in the sum of the target lesions was associated with improved PFS (AHR: 0.77, 95%CI: 0.63-0.94, p-value:0.009) and OS (AHR: 0.62, 95%CI: 0.42-0.93, p-value:0.02). Conclusions: While baseline tumor burden volume was not associated with clinical outcome to immunotherapy-based therapy in patients with metastatic RCC; however, the degree of early tumor shrinkage was significantly associated with better outcomes. Large tumor burden does not preclude response and good outcome to immunotherapies.
Real-world analysis of outcomes of patients receiving bevacizumab for recurrent glioblastoma in British Columbia.
Authors: Manik Chahal, Rebecca A. Harrison, Brian Arthur Thiessen
Journal: Journal of Clinical Oncology (2022)

e14017 Background: Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev to evaluate treatment practices and outcomes. Methods: Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2017 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test. Results: 182 patients were reviewed. There were 180 reported deaths with median PFS 3 months (CI 95 = 2.5 - 3.5) and OS 7 months (CI 95 = 6.2-7.8) from Bev initiation. Higher corticosteroid dose prior to Bev initiation was associated with worse OS on univariate and multivariate analysis ( p = 0.40 and 0.01, respectively). 67% of patients on corticosteroids reduced their dose shortly after Bev initiation. Most patients (68%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev &lt; 6 months from completion of chemoradiation (prior to adjuvant temozolomide completion) had improved PFS ( p = 0.02) and OS compared to those who started Bev later ( p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes ( p = 0.09). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy ( p = 0.10). Conclusions: Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Therefore, further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.
Clinical characteristics and outcome of a large cohort of patients with primary central nervous system (CNS) tumors and tropomyosin receptor kinase (TRK) fusion.
Authors: Audrey-Anne Lamoureux, Michael J. Fisher, Lauriane Lemelle, Elke Pfaff, Stefan M. Pfister, Dominik Sturm, David T.W. Jones, Daniel Orbach, Scott Raskin, Alexander E. Drilon, Michal Zapotocky, Christina Coleman Abadi, Marc Barritault, Pierre Leblond, Uri Tabori, Jordan R. Hansford, Craig Erker, Francois Doz, Theodore Willis Laetsch, Sébastien Perreault
Journal: Journal of Clinical Oncology (2022)

2052 Background: TRK fusions are detected in less than 3% of central nervous system (CNS) tumors. Given their rarity, there are limited data on the clinical course of affected patients. Methods: We contacted 166 oncology centers worldwide to retrieve data on patients with TRK fusion-driven CNS tumors. Data extracted included demographics, histopathology, TRK gene fusion, treatment modalities and outcomes. Results: Ninety-two patients with TRK fusion-driven primary CNS tumors were identified including 76 pediatric patients (82.6%), 15 adults (16.3%) and 1 not specified (1.1%). Median age at diagnosis was 4.4 years (range 0.0–78.3) and 58.7 % were male. NTRK2 gene fusions were found in 45 patients (48.9%), NTRK1 and NTRK3 aberrations were detected in 27 (29.3%) and 20 (21.7%), respectively. Tumor types included 56 high-grade gliomas (HGG; 60.9%), 20 low-grade gliomas (LGG; 21.7%), 4 embryonal tumors (4.3%) and 12 others (13.0%). Median follow-up was 40.5 months (range 3–226). During the course of their disease, 75 (81.5%) patients underwent surgery with a treatment intent, 67 (72.8%) patients received chemotherapy, 50 (54.3%) patients received radiation therapy, while 47 (51.1%) patients received NTRK inhibitors (6 as first line treatment). There were significant differences in the median progression-free (PFS) and overall survival (OS) between pediatric patients compared to adults. The pediatric median PFS was 32 months (95% CI: 15.5–48.5) compared to 8 months for the adult (95% CI: 4.5–11.5, p = 0.015). The pediatric median OS was 182 months (95% CI: 25.1–338.9) compared to 24 months (95% CI: 18.3–29.7 p &lt; 0.001) for adult patients. There was no difference in the PFS of LGG compared to HGG. However, the OS was significantly worse for the HGG when compared to LGG (p = 0.039). The median OS for LGG was not reached and the median OS for HGG was 70 months (95% CI 7.5–132.5). Nineteen patients with HGG (38.0 % 19/50 evaluable patients) died compared to only one patient with LGG (5.6% 1/18 evaluable patients, p = 0.014). Conclusions: We report the largest cohort of patients with TRK fusion-driven primary CNS tumors. These results will help us to better understand clinical evolution and compare outcomes with ongoing clinical trials.
Molecular characterization of cancers with <i>ALK</i> gene fusions in nonlung tumors.
Authors: Jin Zhang, Yushuai Han, Weiran Wang, Mengxiang Xu, Jianhua Zhu, Tonghui Ma
Journal: Journal of Clinical Oncology (2022)

3121 Background: ALK gene rearrangement is known as “diamond mutation”. Targeted tyrosine kinase inhibitors have perfect therapeutic effects on ALK fusion lung cancer patients (pts), but the molecular characteristics of ALK fusions in other cancers have not been systematically elucidated. Methods: We retrospectively analyzed the NGS data of ALK fusion-positive Chinese tumor pts (n = 1068) to characterize ALK fusions in pan-cancer (excluding lung cancer) pts. Results: A total of 66 ALK fusion-positive pts with 13 types of cancer (excluding lung cancer) were screened, including 0.4% (24/5800) of brain tumor pts, 0.1% (11/7725) of gastrointestinal cancer pts, 0.4% (7/1741) of thyroid cancer pts, 0.5% (8/1732) of sarcoma pts, 0.2% (4/2031) of liver cancer pts, 0.6% (3/540) of melanoma pts, 9% (2/22) of inflammatory myofibroblastic tumor pts, 2.5% (2/79) of embryonal tumor pts, 0.4% (1/282) of lymphoma pts, 3.2% (1/31) of parotid carcinoma pts, 0.1% (1/985) of breast cancer pts, 0.4% (1/241) of prostatic cancer pts and 0.3% (1/320) of ovarian cancer pts. Herein, we reported 28 ALK fusion patterns, of which the most common partners were EML4 (n = 24) and STRN (n = 8), and mainly occurred in brain tumors (14/24, 58.8%) and thyroid cancers (6/8, 75%), respectively. In addition, there were 8 ALK fusion modes that were never reported before. Of the ALK fusion patterns described above, 92.4% (61/66) of fusions were located at the most canonical site of ALK (exon20), preserving the intact kinase domain. Meanwhile, rare fusion positions in the ALK gene were also found, such as PPP1CB-ALK(ex2:ex4), NUP107-ALK(ex20:ex3), COL14A1-ALK(ex8:ex4), BRAF-ALK(ex9:ex4), which preserve the extracellular and transmembrane domains, as well as RASD2-ALK(ex2:ex24), of which the breakpoint in ALK gene may disrupt the formation of kinase domain. Conclusions: We demonstrated the rarity of ALK gene fusions in nonlung cancers. Analyzing the ALK fusion characteristics of these cancer may help to clarify their pathogenesis and provide ideas for new drug treatment.[Table: see text]
Evaluating predictors of food insecurity among patients with cancer in the safety-net setting.
Authors: Ana I. Velazquez Manana, Hala Borno, Evelin Trejo, Sylvia Zhang, Abigail A. Rodriguez Saldana, Ivan C. Leung, Hilary K. Seligman, Tracy Kuo Lin
Journal: Journal of Clinical Oncology (2022)

e18550 Background: Patients with cancer, especially minority and low-income individuals, are at increased risk of financial toxicity and food insecurity. The COVID-19 pandemic has added dire economic challenges to vulnerable populations leading to a global increase in food insecurity. We sought to evaluate the severity and predictors of food insecurity among low-income patients with cancer. Methods: We conducted a cross-sectional multi-lingual survey (i.e., English, Spanish, and Chinese) on a convenience sample of patients with cancer who receive oncologic care at a safety-net hospital. Food insecurity and financial toxicity were measured using validated scales [i.e., US Department of Agriculture Household Food Security Survey and the Comprehensive Score for Financial Toxicity (COST)]. The primary outcome was food insecurity during COVID-19 and predictors of interest included sex, financial toxicity, insurance change, and degree of acculturation. Data was summarized using descriptive statistics and we explored associations between food insecurity and predictors of interest using bivariate regression. Results: A total of 140 patients participated in the study, of whom 56% were male and 47% were 50-64 years old. The most common cancer diagnoses were breast cancer (33%), followed by prostate (13%) and lung cancer (12%). The diverse study participants self-reported being 42% Hispanic/Latinx, 33% Asian, 18% Black or African American, and 14% White. Over half (52%) reported an annual household income ≤$24,999 and 50% experienced a decrease in income during the COVID-19 pandemic. The median COST score was 24 (IQR: 19-31) with 41% experiencing financial toxicity (COST &lt; 26). Most participants experienced food insecurity, including 42% with low food security and an additional 19% with very low food security. In bivariate analysis, increasing financial toxicity (i.e., lower COST score) was associated with a 21% increased risk of very low or low food security (95% CI: 1.11-1.32) and 13% increased risk of low food security (95% CI: 1.05-1.21). Male sex was associated with 312% increased risk of very low food insecurity when compared to female sex (95% CI: 1.02-9.55). Acculturation and changes in insurance coverage were not associated with increased risk of food insecurity. Conclusions: Food insecurity was highly prevalent in this multi-ethnic cohort of low-income patients with cancer. Interestingly, male sex was significantly associated with increased risk of very low food insecurity. Further analyses should explore this potentially at-risk population, their access to nutrition-related support, and the impact of food insecurity in cancer outcomes.
<i>In vitro</i> and <i>in vivo</i> investigations of anlotinib in bladder cancer treatment.
Authors: Zeji Meng, Xinqi Pei, Yanan Gu, Lei Li, Dalin He, Kaijie Wu
Journal: Journal of Clinical Oncology (2022)

e16505 Background: Bladder cancer is one of the most common malignancy in urinary system. Fibroblast growth factor receptor 3 (FGFR3) is the most common alteration gene in bladder cancer, occurring in approximately 70% of non-metastatic bladder cancer and 20% of metastatic bladder cancer. Anlotinib is a potent oral, multi-target tyrosine kinase inhibitor with a favorable safety which mainly targets vascular endothelial growth factor receptor (VEGFR), FGFR, platelet-derived growth factor receptors, and c-kit. This study aims to investigate the role of anlotinib in bladder cancer compared with FGFR3 inhibitor erdafitinib i n vitro and in vivo. Methods: MTT, colony formation, and Transwell assays were performed on bladder cancer cells (SW780 and UMUC14) to confirm the effects of anlotinib and erdafitinib on proliferation, migration and invasion. Apoptotic effect was evaluated by Annexin V/propidium iodide double staining, and the levels of the protein and mRNA were examined by RNA-seq, Western blotting and RT-qPCR. Finally, mice with palpable xenografts were treated either with anlotinib and erdafitinib for 8 days before they were sacrificed for measuring the sizes and weights of the tumors. Results: To assess the roles of anlotinib in bladder cancer, we treated SW780 cell line which had FGFR3-BALAP2L1 fusion mutation and UMUC-14 cell line which had a FGFR3 (MuS247C) mutation with DMSO, anlotinib and erdafitinib. As seen in MTT, colony formation and Transwell assays, anlotinib repressed cell proliferation, migration and invasion as erdafitinib. Compared with vehicle, Anlotinib promoted cell apoptosis of bladder cancer cells. To further explore the mechanism, anlotinib and erdafitinib suppressed p-Erk1/2 and p-AKT, while only anlotinib inhibited the expression of VEGF-a. Compared with erdafitinib, the inhibitory ability of anlotinib was weaker than that of erdafitinib in cell line with FGFR3 (MuS247C) mutation, on the contrary, it was much stronger in cell line with FGFR3-BALAP2L1 fusion mutation. In addition, the in vivo data from xenagrafts also supported that anlotinib could significantly repress tumor growth with FGFR3 fusion mutation, and the efficacy was better than erdafitinib. Conclusions: Anlotinib could repress the proliferation, migration and invasion of bladder cancer cells by inhibiting the phosphorylation of Erk1/2 and AKT, and the suppression VEGF-a expression, whose effects was better than erdafitinib in bladder cancer with FGFR3 fusion mutation. Therefore, anlotinib might be a potential novel targeted agent to treat the bladder cancer patients with FGFR3 fusion mutations, and clinical trials are needed for further investigation.